Healthy Skepticism International News
Keller citations update
Analysis of 39 papers/letters available since our 2008 analysis that cite the Keller paper
Jon Jureidini & Elsa Jureidini, July 2010.
1. Published papers that unequivocally report study 329 as positive on the basis of the Keller paper.| Paper | All content pertaining to Keller paper (see hyperlinks for tables) |
| 1. Reed, AL., Anderson, JC., Bylund, DB., et al. 2009. Treatment with escitalopram but not desipramine decreases escape latency times in a learned helplessness model using juvenile rats. Psychopharmacology. 205(2):249-59. | Although some selective serotonin reuptake inhibitors (SSRIs) have been shown to be effective for treating pediatric depression (Emslie et al. 1997; Keller et al. 2001; March et al. 2004), there has been controversy surrounding the use of SSRIs in young patients due to a possible increase in suicidal ideation during treatment. |
| 2. Landsverk, J.A., Burns, B.J., Stambaugh, L.F., et al. 2009. Psychosocial Interventions for Children and Adolescents in Foster Care: Review of Research Literature. Child Welfare. 88(1):49-69. | RCTs comparing SSRIs to placebo for child and adolescent depression have produced significant, positive findings in four studies (Emslie, Rush, Weinberg, Kowatch, Hughes, Carmody, & Rintelmann, 1997; Keller, Ryan, Strober, Klein, Kutcher, Birmaher, Hagino, Koplewicz, Carlson, Clarke, Emslie, Feinberg, Geller, Kusumakar, Papatheodorou, Sack, Sweeney, Wagner, Weller, Winters, Oakes, & McCafferty, 2001; Strober DeAntonio, Schmidt-Lackner, Pataki, Freeman, Rigali, & Rao, 1999; Wagner, Ambrosini, Rynn, Wohlberg, Yang, Greenbaum, Childress, Donnelly, & Deas, 2003) and positive but not statistically significant findings in one study (Simeon, Dinicola, Ferguson, & Copping, 1990). |
| 3. Ekinci, O., Titus, J.B., Rodopman, A.A., et al. 2009. Depression and Anxiety in Children and Adolescents with Epilepsy: Prevalence, Risk Factors and Treatment. Epilepsy & Behaviour. 14(1):8-18. | A number of open-label and randomized placebo-controlled studies have been performed to date that demonstrate the efficacy and safety of the selective serotonin reuptake inhibitor (SSRI) group of antidepressants (i.e., fluoxetine, paroxetine, citalopram,and sertraline) in children and adolescents with depression. Response rates as high as 60% have been reported [117–120]. |
| 4. David-Ferdon, C. & Kaslow, N.J. 2008. Evidence-Based Psychosocial Treatments for Children and Adolescent Depression. Journal of Child and Adolescent Psychology. 37(1):62-104. | There is a burgeoning literature of randomized controlled trials documenting the efficacy of various pharmacological interventions with depressed youth, particularly adolescents. Positive effects have been for fluoxetine (Prozac; Emslie et al., 2002; Emslie & Mayes, 2001; Emslie et al., 1997; TADS Team, 2004), paroxetine (Paxil; Keller et al., 2001), sertraline (Zoloft; Wagner et al., 2003), and escitalopram (Lexapro; Wagner, Jonas, Findling, Ventura, & Saikali, 2006; Wagner et al., 2004). |
| 5. Cummings, C.M. & Fristad, M.A. 2007. Medications Prescribed for Children with Mood Disorders: Effects of a Family-Based Psychoeducation Program. Experimental and Clinical Psychopharmacology. 15(6):555-62. | Selective serotonin reuptake inhibitors have become the first line of pharmacological treatment for children with depression because of their reported effectiveness and their relatively few side effects (Birmaher & Brent, 2002; Emslie et al., 1997; Keller et al., 2001). |
| 6. Alacqua, M., Trifiro, G., Arcoraci, V., et al. 2008. Use and Tolerability of Newer Antipsychotics and Antidepressants: A Chart Review in a Paediatric Setting. Pharmacy World & Science. 30(1):44-50. | Several large-scale clinical studies have shown that SSRIs are effective in treating depression, anxiety and obsessive compulsive disorders of children and adolescents [10–13]. |
| 7. Kronenberg S, Frisch A, Rotberg B, et al. 2008. Pharmacogenetics of selective serotonin reuptake inhibitors in pediatric depression and anxiety. Pharmacogenomics 9(11):1725-1736 | there are now several large, well-conducted, double-blind, placebo-controlled trials establishing the efficacy of selective serotonin reuptake inhibitors (SSRIs) in the treatment of child and adolescent depression, obsessive-compulsive disorder (OCD) and non-OCD anxiety disorders [10-18]. |
| 8. Tao, RR., Emslie, G. & Mayes, T. 2010. Pharmacotherapy for Pediatric Major Depression. Psychiatric Annals. 40(4):192-202. | Although one trial of paroxetine in adolescents showed benefit over placebo on some outcomes,27 two other RCTs of paroxetine were negative in treating pediatric depression.28 |
| 9. Masi, G., Liboni, F. & Brovedani, P. 2010. Pharmacotherapy of Major Depressive Disorder in Adolescents. Expert Opin. Pharmacotherp. 11(3):376-86. | Paroxetine has been shown to have antidepressant activity in adolescents on some secondary measures, but not in main outcome measures (40), whereas two other studies did not demonstrate efficacy versus placebo (41,42). |
| 10. Ghasemi, M., Montaser-Kouhsari, L., Shafaroodi, H. Et al. 2009. NMDA receptor/nitrergic system blockage augments antidepressant-like effects of paroxetine in the mouse forced swimming test. Psychopharmacology. 206:325-33. | Paroxetine hydrochloride is one of the most potent inhibitors of the reuptake of serotonin (5-hydroxytryptamine [5-HT]) of all the currently available antidepressants including the class of SSRIs with currently approved indications for the treatment of depression, obsessive–compulsive disorder, panic disorder, and social anxiety (Anderson 2000; Ballus et al. 2000; Bourin et al. 2001; Chaudhry et al. 2002; Claghorn et al. 1992; Emslie et al. 2006; Danish University Antidepressant Group 1990; Keller et al. 2001; Nemeroff 1993; Rapaport et al. 2003; Yonkers et al. 2008). |
| 11. Lenz, K., Coderre, K., Watanabe, MD 2009. Overview of Depression and its Managment in Children and Adolescents. Formulary. 44(6):172-80. | Table 2: SSRI dosing recommendations for pediatric patients (see table sheet) |
| 12. Williams, S.B., O’Connor, E.A., Eder M., et al. 2009. Screening for Child and Adolescent Depression in Primary Care settings: A Systematic Evidence Review for the US Preventive Services Task Force. Pediatrics. 123(4):e716-35. |
Table 2. Characteristics of RCTs of Depression Treatment in Children and Adolescents (KQ4) (see table sheet) Figure 2. Response to SSRIs to treat MDD in RCTs including children and adolescents (KQ4) (see table sheet) |
| 13. Tsapakis, E.M., Soldani, F., Tondo, L., et al. 2008. Efficacy of Antidepressants in Juvenile Depression: Meta-Analysis. British Journal of Psychiatry. 193(1):10-7. |
A
total of 3069 participants were represented, not counting 91 placebo-treated
participants in the study by Keller et al39 considered twice in
placebo comparisons with an SRI or tricyclics antidepressant (online Table
DS1). The weighted mean participant age was 13.5 years (s.d.=0.4, median=14.5, range 6–20). Most trials with both
children and adolescents did not report response rates for each age group
separately. We also excluded the alprazolam arm of
one study,22 and two arms involving unmasked psychotherapy with or without fluoxetine in another.5 Of the remaining 29 studies, 5
were reported as abstracts or summaries from meetings, the US Food and Drugs
Administration website or corporate websites.35,37,39,41 One report
included data from two trials of the atypical antidepressant mirtazapine,39
and another contained results from two trials of the SRI-like agent
venlafaxine.44 Figure 2 – see table sheet. |
| 14. Dudley, M., Hadzi-Pavlovic, D., Andrews, D., et al. 2008. New-Generation Antidepressants, Suicide and Depressed Adolescents: How Should Clinicians Respond to Changing Evidence? Australian and New Zealand Journal of Psychiatry. 42(6):456-66. |
Randomized clinical trials (RCTs) of fluoxetine (41,42), sertraline (43) and paroxetine (44) concluded that SSRIs were beneficial in children. A trial of paroxetine (44) was positive on several secondary end-points but not the primary outcome, while two sertraline trials had a positive primary end-point only when their data were pooled and analysed (43). |
| 15. Antonuccio, D. 2008. Treating Depressed Children with Antidepressants: More Harm than Benefit? Journal of Clinical Psychology in Medical Settings. 15(2):92-7. | Six of the seven published randomized controlled studies of the efficacy of SSRIs in children and adolescents report significant differences on some measures, suggesting SSRIs may work better (Emslie et al., 1997, 2002; Keller et al., 2001; Simeon, Dinicola, Fergueson, & Copping, 1990; TADS, 2004; Wagner et al., 2003; Wagner et al., 2004). |
| 16. Usala, T., Clavenna, A., Zuddas, A. & Bonati, M. 2008. Randomised Controlled Trials of Selective Seretonin Reuptake Inhibitors in Treating Depression in Children and Adolescents: A Systemic Review and Meta-Analysis. European Neuropsychopharmacology. 18(1):62-73. |
Thirteen relevant randomised
controlled trials of SSRI treatment of depression in children and
adolescents, published in 12 papers (Wagner et al., 2003; Simeon et al., 1990; Emslie et al.,
1997, 2002; March et al., 2004; Braconnier et al., 2003; Keller et al., 2001; Berard et al., 2006; Emslie et
al., 2006b; Von Knorring et al., 2006; Wagner et
al., 2004, 2006), therefore met
the criteria for inclusion in the systematic review. Table 1 Characteristics of randomised controlled trials of SSRIs for the treatment of depression in children and adolescents (see table sheet) Table 2 Assessment tools and inclusion criteria used in the reviewed RCTs (see table sheet) K-SADS Present and Lifetime Version (K-SADS-PL; Kaufman et al., 1997) was used in 5 studies, and the Lifetime Version (K-SADS-L) (Keller et al., 2001) and the K-SADS-P in one each (Von Knorring et al., 2006). In one study on paroxetine (Keller et al., 2001), both in the published paper and in the protocol available on the Glaxo website (http://www.gsk.com/media/paroxetine.htm), 2 primary outcome measures were reported: 1. score ≤8 or a ≥50% reduction in baseline HAM-D score at the end of treatment; 2. change from baseline in HAM-D total score. In the published paper, however, the authors discussed results related to only HAM-D score ≤8, and the previously declared complete primary efficacy measures were only reported after the secondary ones. A weak improvement in efficacy was observed in 4 studies (Wagner et al., 2003, 2006; Keller et al., 2001; Berard et al., 2006) and a reduction in 1 (Wagner et al., 2004). In one paroxetine study (Keller et al., 2001), the CGI-I odds ratio changed, indicating a greater improvement in the active treatment group compared to HAM-D odds ratio (from 1.48 to 1.86, using HAM-D and CGI-I, respectively) whereas in another (Wagner et al., 2004) the odds ratio changed from 1.70, using CDRS-R, to 1.02, using CGI-I. Differently from studies on tricyclic antidepressants (Hazell et al., 2002), in which a trend toward responsiveness is related to increasing age, this factor does not appear to correlate with outcome in the present meta-analysis: the results of the three studies involving only adolescents (two with paroxetine, one with fluoxetine) were conflicting (March et al., 2004; Keller et al., 2001; Berard et al., 2006). Most studies reviewed here did not exclude patients with first-degree relatives with bipolar disorder (Wagner et al., 2003, 2004, 2006; Keller et al., 2001; Von Knorring et al., 2006) and some studies did not even consider bipolar disorder as an exclusion criterion. Figure 1 Random effects meta-analysis of primary outcome between SSRI treatment and placebo groups (see table sheet) |
| 17. Stewart, JW., McGrath, PJ., Quitkin, FM & Klein, DF. 2009. DSM-IV Depression with Atypical Features: Is It Valid? Neuropsychopharmacology. 34:2625-32. | TCAs have not been shown to be effective in general in adolescents (Geller et al, 1999; Hazell et al, 2002), or in depressed adolescents with atypical features (Klein et al, 1998) whereas SSRIs have generally not been effective for depressive illness in children (Mandoki et al, 1997; Keller et al, 2001; Whittington et al, 2004; Wagner et al, 2006) except fluoxetine (Emslie et al, 1997; Emslie et al, 2002; Whittington et al, 2004). |
| 18. Malkesman, O. & Weller, A. 2009. Two different putative genetic animal models of childhood depression – A review. Progress in Neurobiology. 88:153-69. |
Depressed
children and adolescents do not show evidence of hypercortisolemia
as frequently as is reported in depressed adults (Kaufman
and Ryan, 1999; Ryan and Dahl, 1993), and most notably, depressed
children fail to respond to antidepressant treatment as well as adults do (Hazell et al., 1995; Keller et al., 2001). For example most of the trials with tricyclic antidepressants in both children (Geller et al.,1989; Puig-Antich et al., 1987; Kashani et al., 1984; Petti and Law, 1982; Kye and Ryan, 1995; Keller et al., 2001) and adolescents (Birmaher et al., 1998; Klein et al., 1998; Kramer and Feiguine, 1981; Kutcher et al., 1994; Kye et al., 1996; Keller et al., 2001;Geller et al., 1990) have not been shown to be more efficacious than placebo, and only 3 (20%) of 15 antidepressant trials submitted to the FDA for pediatric depression demonstrated superiority of drug over placebo (Hammad et al., 2006). The monoamine theory for depression may be even less relevant, or at least different than in the adult in the case of childhood depression, since depressed children fail to respond to antidepressant treatments (developed based on the monoamine theory) as well as adults do (Hazell et al., 1995; Kye and Ryan, 1995; Keller et al., 2001). In sum, we speculate that the different and unique abnormal monoamine patterns exhibited by the ‘‘depressive-like’’ prepubertal rats from the different strains compared to their adults may be the biological basis for the failure of depressed children to respond to antidepressant treatment in contrast to adults (Hazell et al., 1995; Keller et al., 2001), thus highlighting the contribution of other non-monoaminergic factors to childhood depression and its treatment (Possel and Hautzinger, 2006). In contrast to adults, most depressed children fail to respond to antidepressants (Hazell et al., 1995; Keller et al., 2001). For example, tricyclics antidepressants were not more efficacious than placebo for treating pediatric depression (Kye and Ryan, 1995; Keller et al., 2001). |
| 19. Belitz, J. & Bailey, R.A. 2009. Clinical Ethics for the Treatment of Children and Adolescents: A Guide for General Psychiatrists. Psychiatric Clinics of North America. 32(2):243-57. | Medications with proven efficacy in adults may not demonstrate such efficacy in children.13 |
| 20. Cohen, D., Deniau, E., Maturana, A. et al. 2008. Are Child and Adolescent Respones to Placebo Higher in Major Depression than in Anxiety Disorders A Systematic Review of Placebo-Controlled Trials. PLoS ONE 3(7):e2632. | Table 1. Placebo response rates in double-blind placebo-controlled trials for internalized disorders in children and adolescents (See table sheet) |
| 21. Malkesman, O., Braw, Y., Ram, E., et al. 2008. Dehydroepiandrosterone and Monoamines in the Limbic System of a Genetic Animal Model of Childhood Depression. European Neuropsychopharmacology. 18(4):255-61. |
Most
notably, depressed prepubertal children fail to
respond to antidepressant treatment as well as adults do (Hazell et al.,
1995; Keller et al., 2001; Zalsman et al., 2006).
For example tricyclics antidepressants have not been shown to be more
efficacious than placebo for pediatric depression (Kye and Ryan, 1995; Keller et al., 2001) Since antidepressants developed to affect dopamine and serotonin levels fail to help children suffering from depression in the same percentage as in adults (Hazell et al., 1995; Keller et al., 2001; Kye and Ryan, 1995), and since several studies found a strong connection between serotonin, dopamine and DHEA we also measured the levels of these monoamines in these regions in order to examine unique developmental characteristics in the monoamines system. These different abnormal monoamine patterns between the "depressed" prepubertal rats and their adults, may help to explain why depressed children and adolescents fail to respond to antidepressant treatment as well as adults do (Hazell et al., 1995; Keller et al., 2001). The difference in abnormal monoamine patterns between the "depressed" prepubertal rats found in the current study, and in adults (found in several studies, Zangen et al., 1997, 1999; Yadid et al., 2001) may represent the biological basis for why depressed children and adolescents fail to respond to antidepressant treatment in contrast to adults (Hazell et al., 1995; Keller et al., 2001), and might imply that other non-monoaminergic factors, such as DHEA contribute to childhood depression (Possel and Hautzinger, 2006). |
| 22. Wagner KD, Emslie GJ, Kowatch RA, et al. An Update on Depression in Children and Adolescents. Journal of Clinical Psychiatry 2008, 69:1818-1828 | Medications that have failed to demonstrate statisitically significant superiority to placebo on primary efficacy measures in pediatric depression studies include paroxetine53-55 |
| 23. Bailly, D. 2008. Benefits and Risks of Using Antidepressants in Children and Adolescents. Expert Opinion on Drug Safety. 7(1):9-27. |
In the first study, Keller et al. evaluated
the efficacy of paroxetine and imipramine
compared with placebo in 275 adolescents aged 12 – 18 years. On the primary
outcome measures, neither paroxetine nor imipramine was found superior to placebo. On the
secondary outcome
measures, only paroxetine
demonstrated a significant difference in CGI response rate over placebo (65% vs. 48%; p = 0.02) [36]. In their critical analysis, Jureidini et al. questioned the quality of reporting data about adverse events in the DBPC trials of SSRIs [10] . For example, of 93 patients treated with paroxetine by Keller et al. , 11 (12%) had serious adverse events, compared with 2/87 (2%) in the placebo group [36]. In two DBPC trials of paroxetine [36] and sertraline [80] , PAEs were reported in 17 and 37% of children and adolescents, respectively, receiving the active drug. |
| 24. Malkesman, O., Shayit, M., Genud, R., et al. 2007. Dehydroepiandrosterone in the Nucleus Accumbens is associated with Early Onset of Depressive-Behaviour: A Study in an Animal Model of Childhood Depression. Neuroscience. 149(3):573-81. |
In contrast to adults, most depressed prepubertal children fail to respond to antidepressants (Keller et al., 2001). For example, tricyclic
antidepressants were not more efficacious than placebo for treating pediatric
depression (Kye and Ryan, 1995; Keller et al., 2001). Though one should not draw comparisons directly from an animal study to humans, the developmental differences in patterns of NAc monoaminergic activity found in the current study may be relevant to the reported poor response of depressive prepubertal children to antidepressant treatment (Keller et al., 2001). |
| 25. Sartorius, N., Baghai, T.C., Baldwin, D.S., et al. 2007. Antidepressant Medications and Other Treatments of Depressive Disorders: A CINP Task Force Report Based on a Review of Evidence. The International Journal of Neuropsychopharmacology. 10(s1):s1-207. |
Table 22. Published placebo-controlled RCTs of SSRIs and newer antidepressants in children and adolescents (see table sheet) 10.2.1.1.2.2 Paroxetine Keller et al. treated 180 adolescents (aged 12–18) with either paroxetine or placebo in a multi-site, 8-week RCT. The HAMD-17 was the primary outcome measure; both response (end of trial score of f8 or a >50% reduction) and change from baseline were assessed. Whereas youth treated with paroxetine improved on primary outcome measures relative to placebo, these improvements were not statistically significant in the case of imipramine (Keller et al., 2001). Adverse events were reported more often by patients receiving paroxetine (11 patients) versus placebo (2 patients). Additionally, paroxetine-treated patients had an increased risk of suicidal ideation compared with placebo-treated patients (5.4 vs. 0% respectively). |
| 26. Cheung, A.H., Zuckerbrot, R.A., Jensen, P.S., et al. 2007. Guidelines for Adolescent Depression in Primary Care (GLAD-PC): II. Treatment and Ongoing Management. Pediatrics. 120(5):e1313-26. |
TABLE 1 Response Rates in RCTs of Antidepressants Based on Clinical Global Impression (see table sheet) This GLAD-PC–initiated review identified 8 peer-reviewed articles in this area, including 4 trials with fluoxetine,34–37 1 with sertraline,38 1 with citalopram,38 1 with paroxetine,39 and 1 with venlafaxine.40 Overall, fluoxetine has had the largest number of studies with positive results, whereas paroxetine has had the largest number of studies with negative results.34–37,39,42,43 |
| 27. Kersun, L.S. & Elia, J. 2007. Depressive Symptoms and SSRI Use in Pediatric Oncology Patients. Pediatric Blood & Cancer. 49(7):881-7. | TABLE III. SSRI Clinical Trials Outcomes (see table sheet) |
| 28. Spielmans, GI. & Parry, PI. 2010. From Evidence-based Medicine to Marketing-based Medicine: Evidence from Internal Industry Documents. Bioethical Enquiry. 7(1):13-29. | Study 329, sponsored by SKB/GSK, was published in 2001 with a clear message stated in the abstract: "paroxetine is generally well tolerated and effective for major depression in children" (Keller et al. 2001, 762). However, the trial data indicated that the drug was neither efficacious nor particularly safe. |
| 29. Lacasse, JR. & Leo, J. 2010. Ghostwriting at Elite Academic Medical Centers in the United States. PLoS Med 7(2): e1000230. | Study 329, a randomized controlled trial of paroxetine in adolescents, was ghostwritten [4–7] to claim that paroxetine is ‘‘generally well tolerated and effective for major depression in adolescents’’[8], although data made available through legal proceedings show that ‘‘Study 329 was negative for efficacy on all 8 protocol specified outcomes and positive for harm’’ [9]. |
| 30. Jureidini, J.N. & McHenry, L.B. 2009. Key Opinion Leaders and Paediatric Antidepressant Overprescribing. Psychotherapy and Psychosomatics. 78(4):197-201. |
In
2001, Keller et al. [20] published a report of Glaxo-SmithKline’s
study 329 of paroxetine in adolescents that they
claim showed that ‘paroxetine is generally well
tolerated and effective for major depression in adolescents’. Yet we
described how, when the study blind was broken, no significant difference
between paroxetine and placebo was found on the 8 prespecified outcome measures [21] .
The authors omitted from their report several outcome measures specified in
the study protocol, replacing them with positive outcome measures, some of
which were added after the blind was broken. Keller et al. also omitted
details about adverse effects including suicide attempts. GSK celebrated
study 329 as a ‘‘‘cutting-edge" landmark study’ that demonstrated ‘REMARKABLE
efficacy and safety’ to sales
representatives and it continued to spin paroxetine
as superior to placebo in letters to health care professionals up to 2002
[22]. Keller et al. [20] also significantly misrepresented data by claiming a positive response on a primary outcome measure that in fact proved negative, a misrepresentation that was facilitated by the paper being ghostwritten [23]. The publication of the study by Gibbons et al. Distorting the correlation between suicide data and antidepressant prescribing is a major editorial error, and it is hard to see how the misrepresentations in the paper by Keller et al. could have passed editorial scrutiny. |
| 31. Jureidini, J. 2009. How do we Safely Treat Depression in Children, Adolescents and Young Adults? Drug Safety. 32(4):275-82. |
Although
the conclusions of published studies of antidepressants in children were
often favourable, (1-4) it emerged that investigators' conclusions
exaggerated benefits and downplayed adverse effects.(5) While some authors have suggested that these analyses overestimated risk, (26) it appears that the reviewers were very cautious in their analysis. For example, Hammad et al.(7) only designated four patients in GSK's Study 329 (2) as meeting the criteria for their primary outcome of 'suicidal behavior or ideation', allocating a further three cases to the secondary outcome of possible suicidal behavior or ideation'. |
| 32. Schirman, S., Kronenberg, S., Apter, A. et al. 2010. Effectiveness and tolerability of citalopram for the treatment of depression and anxiety disorders in children and adolescents: an open-label study. Journal of Neural Transmission. 117(1):139-45. | The majority of studies evaluated the SSRIs fluoxetine, sertraline and paroxetine (Compton et al. 2001; Keller et al. 2001; Emslie et al. 2002). |
| 33. Bridge, J.A., Birmaher, B., Iyengar, S., et al. 2009. Placebo Response in Randomized Controlled Trials of Antidepressants for Pediatric Major Depressive Disorder. Am J Psychiatry. 166(1):42-9. |
TABLE 1. Characteristics of Placebo-Controlled Trials of Second-Generation Antidepressants in Children and Adolescents With Major Depressive Disorder (see table sheet) In addition, even trial-level data were inconsistently reported, and thus we were unable to examine the impact of several other factors that have been shown to be relevant to clinical response and presumably are relevant to placebo response, such as history of nonresponse to an SSRI, history of abuse, family history of psychiatric disorder, and comorbid psychiatric disorders (23, 39–42). |
| 34. Daviss, W.B. 2008. A Review of Co-Morbid Depression in Pediatric ADHD: Etiologies, Phenomenology, and Treatment. Journal of Child and Adolescent Psychopharmacology. 18(6):565-71. | Investigators in several recent trials of SSRIs in youths with MDD have conducted post hoc analyses of the effects of co-morbid ADHD on depressive response, once again with contradictory findings (Emslie et al. 1997; Birmaher et al. 2000; Keller et al. 2001; Emslie et al. 2002). |
| 35. Marks, D.M., Park, M.H., Ham, B.J., et al. 2008. Paroxetine: Safety and Tolerability Issues. Expert Opinion on Drug Safety. 7(6):783-94. | Neither paroxetine nor placebo was associated with cardiovascular adverse effects [46] , indicating a favourable cardiovascular profile with paroxetine compared to imipramine. |
|
36. Title: World
Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for
biological treatment of unipolar depressive
disorders, part 1: acute and continuation treatment of major depressive
disorder Author(s): Bauer M, Whybrow PC, Angst J, et al. Source: REVISTA DE PSIQUIATRIA CLINICA Volume: 36 Pages: 17-57 Supplement: Suppl. 2 Published: 2009 Times Cited: 0 |
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37. Title: Comparison of the effects of desmethylimipramine on behavior in the forced swim test in peripubertal and adult rats Author(s): Pechnick RN, Bresee CJ, Manalo CM, et al. Source: BEHAVIOURAL PHARMACOLOGY Volume: 19 Issue: 1 Pages: 81-84 Published: FEB 2008 |
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38. Title: Do antidepressants really increase suicide rates in childhood and adolescence? Author(s): Silva H, Martinez JC Source: REVISTA MEDICA DE CHILE Volume: 135 Issue: 9 Pages: 1195-1201 Published: SEP 2007 |
Abstract available in English, but article only available in Spanish. |